PGE2 and PGD2 are important COX metabolites that modulate the response of a variety of immune/inflammatory cell types. We hypothesize that differential expression of EP receptor subtypes on individual inflammatory cell types results in activation of distinct signaling pathways that determine the physiologic response of a target cell to PGE2. We also postulate that expression of the EP2 receptor is a major determinant of the immunomodulatory effects of PGE2 in part by regulating RANK, a potent regulator of DC/T-cell action. We further hypothesize that PGE2 stimulation of the EP2 receptor alters the balance of TH1 and TH2 responses towards a TH2 types response. Finally we hypothesize a physiologically important link exists between EP receptor expression and regulation of PGD2 synthesis and action. To test these related hypotheses, the following specific aims are proposed: In Specific Aim 1 we will identify the key EP receptors in the maturation and activation Antigen Presenting Cells and T cells. We will focus on dendritic cells (DCs) and T-cells as the prime target of PG immuno-modulation. We will isolate cells from wild type (wt) and knockout mice and determine the repertoire of PGs synthesized, as well as the receptors present on the cell surface. We will determine the expression levels of both the DP receptor and the PGD synthase in these cell types. Immune cell function will be assessed in purified cell populations in vitro isolated from both wt and knockout mice. In Specific Aim 2 we will explore whether PGE2 modulates the inflammatory/immunosuppressive effects in murine models of immune injury and immune surveillance via the EP2 receptor. We will analyze mouse models of lung inflammation. The Respiratory Syncytial Virus (RSV) infection model is a THI type model of immune response and the ovalbumin allergic sensitization model is a TH2 type model. We will also examine the effects of the EP2 knockout in the Lewis lung carcinoma and Min model of FAP tumor, models known to be modulated by COX metabolites. In Specific Aim 3 we will investigate the cellular mechanism underlying the reduced inflammatory response observed in DP null mice. We will also identify target cell types affected by DP receptor disruption in allergic asthma as well as tumor models.